As discussed previously, C. elegans CED-9 and its mammalian homolog Bcl-2 play central roles in repressing apoptosis. In nematodes, CED-9 does so by binding to and blocking the activation of CED-4. In vertebrates, Bcl-2, residing in the outer mitochondrial membrane, primarily functions to maintain the low permeability of that membrane, preventing cytochrome c and other proteins localized to the intermembrane space (see Figure 12-22) from diffusing into the cytosol and activating apoptotic caspases.

In order to explain how Bcl-2 carries out this function, and how Bcl-2 activity is regulated by trophic factors as well as by many environmental stimuli, we need to introduce several other important members of the Bcl-2 family of proteins. All members of the Bcl-2 family share a close homology in up to four characteristic regions, termed the Bcl-2 homology domains (BH1–4; Figure 21-39). Each of these proteins has either an anti-apoptotic or a pro-apoptotic function. All members of this family participate in oligomeric interactions; many have hydrophobic sequences at their C-termini that can anchor the proteins in the outer mitochondrial membrane.